Methotrexate/Asparaginase Combo for Pediatric AML May Be Effective Salvage Therapy

Combination chemotherapy with sequential administration of methotrexate (MTX) and asparaginase was found to be effective salvage therapy in a small retrospective study of pediatric patients with relapsed or refractory acute myeloid leukemia (AML) treated at St. Jude Children’s Research Hospital in Memphis.

Myeloblasts with Auer rods seen in AML; source: Paulo Henrique Orlandi Mourao

The treatment was well tolerated even in those heavily pretreated with contemporary frontline or salvage therapy, according to the team of researchers led by Hiroto Inaba, MD, PhD, of the department of oncology at St. Jude. Findings were reported in the January issue of Pediatric Blood & Cancer.

Although recent risk-adapted therapeutic approaches (ie, use of cytarabine [Ara-C], anthracyclines, and etoposide) and improved supportive care have increased survival rates to up to 70% in pediatric AML, up to 40% of patients will still experience relapse or refractory disease, the investigators explained. After relapse, risk of anthracycline-induced cardiomyopathy and resistance to chemotherapeutic agents become major obstacles, and the survival rate drops to around 30% even with use of novel agents such as deoxyadenosine analog [3–5], and hematopoietic stem cell transplantation (HSCT). The treatment regimen used in the present study is based on in vitro synergistic antileukemic activity of time sequential combination of the medications. “In addition,” the authors said, “thymidylate synthase inhibition by MTX and the substantial cytotoxic effect of asparaginase in monoblastic leukemia cells suggested the effectiveness in this particular subtype of AML.”

Patients (N = 15; median age, 10.5 years; range, 1.1–18.5 years) with relapsed or refractory AML, who had previously been treated with frontline therapy, salvage chemotherapy, or HSCT, received sequential administration of MTX and asparaginase at St. Jude Children’s Research Hospital from 1999 to 2012. The treatment regimen included an intravenous dose of MTX followed by a dose of asparaginase (intramuscular or intravenous) 24 hours later. The cycle was repeated every 7–10 days. A complete blood count, chemistries (including liver, renal, and pancreatic function tests), and physical examinations were evaluated at least weekly. Triple intrathecal therapy (MTX, hydrocortisone, and cytarabine) and prophylactic antibiotics or antifungal agents were given at the discretion of the treating physician.

Among the 15 patients, a total of 93 courses of MTX/asparaginase were administered, 75 of which were given in an outpatient setting; non-escalating MTX doses of 60–120 mg/m² were given to 14 patients (3 patients with 60 mg/m², 5 patients with 100 mg/m², and 6 patients with 120 mg/m²). Escalating doses were given to a patient who received the initial dose at 60 mg/m² with subsequent increases of 20 mg/m² until a dose of 100 mg/m² was reached.

Six patients responded to treatment (three had morphologic complete remission with incomplete blood count recovery, two had partial remission, and one had stable disease for 16 months), and four are still alive. Three of six responders had monoblastic leukemia and also developed tumor lysis syndrome.

The 1- and 2-year overall survival rates are 35.6% and 17.8%, respectively. The most common adverse event was transient elevation of transaminases (nine patients). Two patients developed pancreatitis. Episodes of febrile neutropenia were rare (two patients).

“We observed effective cytoreductions, especially in monoblastic leukemia with MLL rearrangement, and elevated uric acid, phosphate, and potassium at the same time (ie, tumor lysis syndrome),” the investigators reported.

A potential additional benefit of the regimen is that it is “more affordable and available than the novel nucleoside analogues regimen (eg, clofarabine with or without cytarabine), even in countries with limited resources,” they added.

“This is an interesting study that raises the possibility that sequential administration of methotrexate and asparaginase may provide an approach for the treatment of refractory or relapsed pediatric patients with AML,” commented Leonidas C. Platanias, MD, PhD, deputy director of the Robert H. Lurie Comprehensive Cancer Center and professor of oncology at Northwestern University Medical School, Chicago. “Although the study was small, the findings are encouraging and warrant further study in a larger group of patients.”

The study was supported in part by a grant from the National Institutes of Health and by the American Lebanese Syrian Associated Charities (ALSAC).